Littérature scientifique sur le sujet « Brain chronic hypoperfusion »

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.

Within the aphasia literature, it is common to link location of lesioned brain tissue to specific patterns of language impairment. This has provided valuable insight into the relationship between brain structure and function, but it does not capture important underlying alterations in function of regions that remain structurally intact. Research has demonstrated that in the chronic stage of aphasia, variable patterns of reduced cerebral blood flow (CBF; hypoperfusion) in structurally intact regions of the brain contribute to persisting language impairments. However, one consistent issue in this literature is a lack of clear consensus on how to define hypoperfusion, which may lead to over- or underestimation of tissue functionality. In the current study, we conducted an exploratory analysis in six individuals with chronic aphasia (>1 year post-onset) using perfusion imaging to (1) suggest a new, individualized metric for defining hypoperfusion; (2) identify the extent of hypoperfused tissue in perilesional bands; and (3) explore the relationship between hypoperfusion and language impairment. Results indicated that our individualized metric for defining hypoperfusion provided greater precision when identifying functionally impaired tissue and its effects on language function in chronic aphasia. These results have important implications for intervention approaches that target intact (or impaired) brain tissue.

Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model.

Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury.

Object. Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis. The conceptual basis for therapeutic angiogenesis after plasmid human VEGF gene (phVEGF) transfer has been established in patients presenting with limb ischemia and myocardial infarction. The authors hypothesized that overexpression of VEGF using a gene transfer method combined with indirect vasoreconstruction might induce effective brain angiogenesis in chronic cerebral hypoperfusion, leading to prevention of ischemic attacks. Methods. A chronic cerebral hypoperfusion model induced by permanent ligation of both common carotid arteries in rats was used in this investigation. Seven days after induction of cerebral hypoperfusion, encephalomyosynangiosis (EMS) and phVEGF administration in the temporal muscle were performed. Fourteen days after treatment, the VEGF gene therapy group displayed numbers and areas of capillary vessels in temporal muscles that were 2.2 and 2.5 times greater, respectively, in comparison with the control group. In the brain, the number and area of capillary vessels in the group treated with the VEGF gene were 1.5 and 1.8 times greater, respectively, relative to the control group. Conclusions. In rat models of chronic cerebral hypoperfusion, administration of phVEGF combined with indirect vasoreconstructive surgery significantly increased capillary density in the brain. The authors' results indicate that administration of phVEGF may be an effective therapy in patients with chronic cerebral hypoperfusion, such as those with moyamoya disease.

We studied the effect of hypertension and chronic hypoperfusion on brain parenchymal arteriole (PA) structure and function. PAs were studied isolated and pressurized from 18-wk-old Wistar-Kyoto (WKY18; n = 8) and spontaneously hypertensive stroke prone (SHRSP18; n = 8) and 5-wk-old prehypertensive (SHRSP5; n = 8) rats. In separate groups, unilateral common carotid artery occlusion (UCCAo) was performed for 4 wk to cause chronic hypoperfusion in 18-wk-old WKY (WKY18-CH; n = 8) and SHRSP (SHRSP18-CH; n = 8). UCCAo caused PAs to have significantly diminished myogenic tone (31 ± 3 vs. 14 ± 6% at 60 mmHg; P < 0.05) and reactivity to pressure from WKY18-CH vs. WKY18 animals. The effect of UCCAo was limited to normotensive animals, as there was little effect of chronic hypoperfusion on vascular reactivity or percent tone in PAs from SHRSP18 vs. SHRSP18-CH animals (53 ± 4 vs. 41 ± 3%; P > 0.05). However, PAs from SHRSP18 and SHRSP5 animals had significantly greater tone compared with WKY18, suggesting an effect of strain and not hypertension per se on PA vasoconstriction. Structurally, PAs from SHRSP18 and SHRSP5 animals had similar sized lumen diameters, but increased wall thickness and distensibility compared with WKY18. Interestingly, chronic hypoperfusion did not affect the structure of PAs from either WKY18-CH or SHRSP18-CH animals. Thus PAs responded to UCCAo with active vasodilation, but not structural remodeling, an effect that was absent in SHRSP. The increased tone of PAs from SHRSP animals, combined with lack of response to chronic hypoperfusion, may contribute to the propensity for ischemic lesions and increased perfusion deficit during hypertension.

Alzheimer disease and cerebrovascular accident are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. Hypoperfusion is associated with oxidative imbalance, largely due to reactive oxygen species, which is associated with other age-related degenerative disorders. Recent evidence indicates that a chronic injury stimulus induces the hypoperfusion seen in the microcirculation of vulnerable regions of the brain. This leads to energy failure, manifested by damaged mitochondrial ultrastructure. Mitochondrial derangements lead to the formation of a large number of electron-dense, ¿hypoxic¿ mitochondria and cause the overproduction of mitochondrial DNA (mtDNA) deletions, which is most likely due to double stranded breaks. Additionally, these mitochondrial abnormalities coexist with increased redox metal activity, lipid peroxidation, and RNA oxidation, all of which are well established features of Alzheimer disease pathology, prior to the appearance of amyloid b deposition. Alzheimer disease, oxidative stress occurs within various cellular compartments and within certain cell types more than others, namely the vascular endothelium, which is associated with atherosclerotic damage, as well as in pyramidal neurons and glia. Interestingly, these vulnerable cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels. This evidence strongly suggests that chronic hypoperfusion induces the accumulation of the oxidative stress products. Furthermore, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We, therefore, conclude that chronic hypoperfusion is a key initiator of oxidative stress in various brain parenchymal cells, and the mitochondria appear to be primary targets for brain damage in Alzheimer disease. In this manuscript, we outline a role for the continuous accumulation of oxidative stress products, such as an abundance of nitric oxide products (via the overexpression of inducible and/or neuronal NO synthase (iNOS and nNOS respectively) and peroxynitrite accumulation, as secondary but accelerating factors compromising the blood brain barrier (BBB). If this turns out to be the case, pharmacological interventions that target chronic hypoperfusion might ameliorate the key features of dementing neurodegeneration.

Vascular, especially cerebrovascular, dysfunction may be a critical factor in ageing and dementia. Cerebrovascular impairment due to risk factors such as ageing, stroke, smoking, diabetes and cerebral hypoperfusion has a deterious impact on the normal supply of basic nutrients such as oxygen and glucose to the brain; their absence leads inevitably to neuronal death. The cerebral white matter lesions found in most forms of dementia are reportedly the result of chronic cerebral hypoperfusion. However the temporal and spatial evolution of damage remains unclear. Furthermore, any decrease in the integrity of the blood-brain barrier (BBB) has been hypothesised to be a precocious attack on white matter. The “milieu interieure” the most protected in the body, namely the extracellular fluid of the brain, is no longer maintained homeostatically. The cumulation of these various pathophysiological processes alters cerebral function and it has been postulated that, in the most extreme instances, the outcome of this cascade of nefarious events leads to dementia. This thesis examines the supposition that chronic cerebral hypoperfusion could be responsible for the time-related development of white and grey matter pathology and investigates the relationships between the disturbances in the integrity of the BBB and white matter pathology. Three studies addressed these aims. In the first, chronic cerebral hypoperfusion, induced in male Wistar rats by bilateral common carotid artery occlusion (BCCAo), was chosen as the model to study changes in axons, myelin, perikarya as well as microglial activation. The groups of rats that underwent BCCAo were examined at three hours as well as three, seven, 14 and 28 days after the induction of chronic cerebral hypoperfusion. The microscopic examination revealed that, after three hours post BCCAo, damage was detected only in axons and myelin. In contrast, no visible pathology to the neuronal perikarya or enhancement of activated microglia (compared to the sham group) was observable. Injury in both white and grey matter and enhancement of activated microglia was observed from three days post BCCAo and increased with time post BCCAo. The most severe damage to the white and grey matter and enhancement of microglial activation was detected at seven days post BCCAo. These results would indicate that white matter damage precedes grey matter pathology and the enhancement of activated microglia. In the second study, the integrity of the BBB at three hours (when only white matter pathology was found according to the results of the first study) and seven days post BCCAo (when more severe damage to the white and grey matter was shown) was assessed by the use of MRI on T1-weighted image acquisitions with gadolinium as a tracer for BBB permeability. White matter integrity was measured by MTR maps from MTI acquisitions in four brain structures (corpus callosum, caudatoputamen, the external and internal capsules). No differences in white matter integrity were detected between the BCCAo and sham group at three hours and seven days. No differences in signal enhancement of gadolinium were detected three hours post BCCAo. However, a significant signal enhancement of gadolinium was detected at seven days post BCCAo in the caudatoputamen and in the external capsule. Furthermore, immunohistochemistry revealed a significant enhancement of activated microglia seven days post BCCAo compared to the sham group. This functional and immunohistochemical finding, when taken together, might indicate that chronic cerebral hypoperfusion is not in itself responsible for BBB permeability. Rather, the damage to the white matter caused by cerebral hypoperfusion may be responsible for the dysfunction of the BBB over time. Another point of interest was the evidence that the enhancement of activated microglia may play a critical role in the increased permeability of the BBB. The final study in this thesis aimed to investigate the possible pathway and proteins potentially implicated in white matter damage and BBB permeability. To address this question, protein levels and the expression of genes involved in the apoptotic and nonapoptotic hypoxic pathways were compared to the sham groups (at three hours and seven days after BCCAo), in three brain structures (cortex, corpus callosum and caudatoputamen). The levels of HIF-1α, MMP-2, Caspase-3 and VEGF were unchanged compared to the sham group after BCCAo. However, VEGF mRNA expression was found to be significantly different to the sham group seven days post BCCAo in all the three structures examined. An overexpression of HIF-1α and a significant level of Caspase-3 would indicate the activation of the apoptotic pathway. However, neither of these criteria were met and these negative results suggest that the apoptotic pathway is not implicated in the mechanisms that lead to white matter pathology after cerebral hypoperfusion. Finally, the significant expression of VEGF mRNA, compared to the sham group seven days post BCCAo, may contribute to the time-relate increased permeability of the BBB. The results presented within this thesis provide a body of evidence to support the hypothesis that chronic cerebral hypoperfusion is - at least – causal to the damage to different components of the white matter which precedes either early ischaemic changes to the perikarya or enhancement of activated microglia following BCCAo. The increased permeability of the BBB, which can be related to the significant over-expression of VEGF mRNA (compared to the sham group seven days post BCCAo), does not appear to be primarily responsible for white matter pathology, because the MRI investigations indicated that BBB integrity was not affected after three hours of BCCAo. The increased permeability of the BBB, observed seven days post BCCAo with MRI, seems to be the consequence of increased brain damage; thereafter, there is a time-dependent relationship between increasing BBB permeability and increasing brain pathology. Overall, the studies reported herein, strengthen the initial working hypothesis. The conclusion – and direction for future studies – would be that minimising white matter pathology and protecting components of the BBB represent potential targets to decrease then incidence of neuropsychological function or to obtund the cerebral dysfunction in patients who suffer from chronic cerebral hypoperfusion.

Cerebral small vessel pathology is now known to be associated with the development of cognitive impairment and mild motor impairments such as gait disturbance in a variety of neurodegenerative diseases. This dissertation explores the hypothesis that blood brain barrier dysfunction is an early event in cerebral ischemia and contributes to the development of cerebral small vessel disease (CSVD). A common rodent model of CSVD is permanent bilateral common carotid artery occlusion in the rat. This model was used to study several aspects of the progression of CSVD including the timecourse of blood brain barrier permeability changes following the onset of ischemia, gait disturbance, the expression of tight junction proteins and cytokine expression. It was determined that BBB permeability was elevated for 2 weeks following BCCAO and ischemic rats displayed lower gait velocity. There was no change in expression of TJ proteins. However, ischemic rats had higher levels of some proinflammatory cytokines and chemokines in brain tissue with no obvious changes in plasma levels. The mechanisms underlying the increase in BBB permeability were studied in vitro using artificial barriers made of confluent rat brain microvascular endothelial cells. Cerebral ischemia has been reported to cause an increase in plasma toxicity, likely by elevating the numbers of circulating microparticles (MPs). MPs isolated from the plasma of ischemic rats were applied to artificial barriers where it was found that they act mainly as vectors of TNF-α signaling. MPs induce activation of caspase-3 and the Rho/Rho kinase pathways. It is concluded that most of the increase in barrier permeability is due to apoptosis and disassembly of actin cytoskeleton and disruption of adherens junctions IV and not an increase in transcellular transport. The effects of treatment with the type III phosphodiesterase inhibitor cilostazol on dye extravasation in the brain, glial activation, white matter damage and motor performance were evaluated. It was determined that cilostazol could improve the increased BBB permeability and gait disturbance and microglial activation in optic tract following BCCAO. Also, the effects of treatment with cilostazol on plasma toxicity in vivo (24h and 14d following BCCAO) and artificial barriers (in vitro) were assessed. It was found that cilostazol could reduce plasma toxicity at 24h and improve increased endothelial barrier permeability that is induced by MP treatment respectively. In summary BBB dysfunction occurs in the rat model of chronic cerebral hypoperfusion with no differences in expression of TJ proteins. There is a mild motor disturbance in the form of lower gait velocity following BCCAO. Cytokines released in brain tissue may be associated with pathological consequences following BCCAO while there is no significant difference in plasma levels and circulating MPs may play a role in BBB dysfunction.

Intact white matter is critical for normal cognitive function. In traumatic brain injury (TBI), chronic cerebral hypoperfusion and Alzheimer’s disease (AD) damage to white matter is associated with cognitive impairment. However, these conditions are associated with grey matter damage or with other pathological states and the contribution of white matter damage in isolation to their pathogenesis is not known. Furthermore, TBI is a risk factor for AD and cerebral hypoperfusion is an early feature of AD. It is hypothesised that white matter damage following TBI or chronic cerebral hypoperfusion will be associated with cognitive deficits and that white matter changes after injury contribute to AD pathogenesis. To investigate this, this thesis examined the contribution of white matter damage to cognitive deficits after TBI and chronic cerebral hypoperfusion and furthermore, investigated the role of white matter damage in the relationship between TBI and AD. Three studies addressed these aims. In the first, mild TBI was induced in wild-type mice and the effects on axons, myelin and neuronal cell bodies examined at time points from 4 hours to 6 weeks after injury. Spatial reference learning and memory was tested at 3 and 6 weeks after injury. Injured mice showed axonal damage in the cingulum, close to the injury site in the hours after injury and at 6 weeks, damage in the thalamus and external capsule were apparent. Injured and sham animals had comparable levels of neuronal damage and no change was observed in myelin. Injured animals showed impaired spatial reference learning at 3 weeks after injury, demonstrating that selective axonal damage is sufficient to impair cognition. In the second study mild TBI was induced in a transgenic mouse model of AD and the effects on white matter pathology and AD-related proteins examined 24 hours after injury. There was a significant increase in axonal damage in the cingulum and external capsule and parallel accumulations of amyloid were observed in these regions. There were no changes in tau or in overall levels of AD-related proteins. This suggests that axonal damage may have a role in mediating the link between TBI and AD. The third study used a model of chronic cerebral hypoperfusion in wild type mice and investigated white matter changes after one and two months of hypoperfusion as well as a comprehensive assessment of learning and memory. Chronic cerebral hypoperfusion resulted in diffuse myelin damage in the absence of ischaemic neuronal damage at both 1 and 2 months after induction of hypoperfusion. Hypoperfused animals also showed minimal axonal damage and microglial activation. Cognitive testing revealed a selective impairment in spatial working memory but not spatial reference or episodic memory in hypoperfused animals, showing that modest reductions in blood flow have effects on white matter sufficient to cause cognitive impairment. These results demonstrate that selective damage to white matter components can have a long-term impact on cognitive function as well as on the development of AD. This suggests that minimisation of axonal damage after TBI is a target for reducing subsequent risk of AD and that repair or prevention of white matter damage is a promising strategy for rescuing cognitive function in individuals who have experienced mild TBI or chronic cerebral hypoperfusion.

In this research project we studied signal transduction pathways triggered by cholinergic system and involved in short term and long term memory formation in the CA1 region of the rat hippocampus, focusing on mTOR pathway. We also evaluated memory impairments and molecular and cellular alterations of the neuron-astrocyte-microglia triad in the hippocampus, in three different animal models of neurodegeneration: normal brain aging, acute neuroinflammation induced by LPS infusion and chronic cerebral hypoperfusion induced by bilateral common carotid artery occlusion